The abundance of metabolites related to protein methylation correlates with the metastatic capacity of human melanoma xenografts.
The abundance of metabolites related to protein methylation correlates with the metastatic capacity of human melanoma xenografts.
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DOI：
10.1126/sciadv.aao5268
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发表时间：
2017-11
期刊：
影响因子：
13.6
通讯作者：
DeBerardinis RJ
中科院分区：
文献类型：
--
作者：
Shi X;Tasdogan A;Huang F;Hu Z;Morrison SJ;DeBerardinis RJ
清除组蛋白H3三甲基化标记抑制人黑色素瘤的转移代谢重编程是转化的主要因素，特定的代谢表型与癌基因型、肿瘤进展和转移相关。通过分析17个患者来源的异种移植黑色素瘤模型中的代谢物，我们确定了与肿瘤生物学特征相关的持久代谢组学特征。与BRAF野生型肿瘤相比，BRAF突变型肿瘤具有糖酵解增强的代谢组学和代谢通量特征。从原发部位有效转移的肿瘤具有与蛋白质甲基化相关的代谢物水平升高，包括三甲基赖氨酸（TML）。TML水平与组蛋白H3在Lys9和Lys27处的三甲基化相关，并且这些位点的甲基化在有效转移的肿瘤中也增强。通过基因或基因沉默组蛋白甲基转移酶SETDB 1或EZH2来消除这些标记中的任何一个，对原发性肿瘤生长没有影响，但降低了细胞侵袭性和转移性扩散。因此，代谢物分析可以揭示人黑素瘤细胞转移的靶向表观遗传要求。
Erasing histone H3 trimethylation marks suppresses the metastasis of human melanomas. Metabolic reprogramming is a major factor in transformation, and particular metabolic phenotypes correlate with oncogenotype, tumor progression, and metastasis. By profiling metabolites in 17 patient-derived xenograft melanoma models, we identified durable metabolomic signatures that correlate with biological features of the tumors. BRAF mutant tumors had metabolomic and metabolic flux features of enhanced glycolysis compared to BRAF wild-type tumors. Tumors that metastasized efficiently from their primary sites had elevated levels of metabolites related to protein methylation, including trimethyllysine (TML). TML levels correlated with histone H3 trimethylation at Lys9 and Lys27, and methylation at these sites was also enhanced in efficiently metastasizing tumors. Erasing either of these marks by genetically or pharmacologically silencing the histone methyltransferase SETDB1 or EZH2 had no effect on primary tumor growth but reduced cellular invasiveness and metastatic spread. Thus, metabolite profiling can uncover targetable epigenetic requirements for the metastasis of human melanoma cells.
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影响因子：
64.5
作者：
Huang H;Sabari BR;Garcia BA;Allis CD;Zhao Y
通讯作者：
Zhao Y
影响因子：
64.8
作者：
Jiang L;Shestov AA;Swain P;Yang C;Parker SJ;Wang QA;Terada LS;Adams ND;McCabe MT;Pietrak B;Schmidt S;Metallo CM;Dranka BP;Schwartz B;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
DOI：
10.1073/pnas.1111312108
发表时间：
2011-09-20
影响因子：
11.1
作者：
Alexander, Peter B.;Wang, Jian;McKnight, Steven L.
通讯作者：
McKnight, Steven L.
影响因子：
45.3
作者：
Balch, Charles M.;Gershenwald, Jeffrey E.;Sondak, Vernon K.
通讯作者：
Sondak, Vernon K.
影响因子：
13.6
作者：
DeBerardinis RJ;Chandel NS
通讯作者：
Chandel NS